ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.742C>A (p.Leu248Met)

gnomAD frequency: 0.00004  dbSNP: rs780389237
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001183922 SCV001349770 uncertain significance Cardiomyopathy 2023-04-21 criteria provided, single submitter clinical testing This missense variant replaces leucine with methionine at codon 248 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/281422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001244427 SCV001417647 uncertain significance Arrhythmogenic right ventricular dysplasia 5 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 248 of the TMEM43 protein (p.Leu248Met). This variant is present in population databases (rs780389237, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 923336). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001529347 SCV001996910 uncertain significance not provided 2019-11-11 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics RCV002379711 SCV002668507 uncertain significance Cardiovascular phenotype 2019-03-05 criteria provided, single submitter clinical testing The p.L248M variant (also known as c.742C>A), located in coding exon 9 of the TMEM43 gene, results from a C to A substitution at nucleotide position 742. The leucine at codon 248 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002505782 SCV002814366 uncertain significance Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3 2021-07-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001529347 SCV003799420 uncertain significance not provided 2022-04-26 criteria provided, single submitter clinical testing The TMEM43 c.742C>A; p.Leu248Met variant (rs780389237), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 923336). This variant is reported in the non-Finnish European population with an overall allele frequency of 0.006% (8/128,976 alleles) in the Genome Aggregation Database. The leucine at codon 248 is moderately conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.181). Due to limited information, the clinical significance of the p.Leu248Met variant is uncertain at this time.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529347 SCV001742628 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001529347 SCV001969919 likely benign not provided no assertion criteria provided clinical testing

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